Brain hemorrhage is the most fatal form of stroke. For patients with both intracerebral (ICH) and intraventricular (IVH) hemorrhages, community mortality is consistently reported at 50-80% with no validated, efficacious treatment. Animal models demonstrate substantial physiologic and functional benefit when blood is removed rapidly from the ventricle; our human trial data show similar mortality and functional benefit trends with blood removal. Current therapy which uses extraventricular drainage (EVD) neither improves long-term survival nor alters the effect of blood on tissue. Adding recombinant tissue plasminogen activator (rt-PA) may be the key to a rapid, effective, and safe means for blood removal that limits brain tissue injury, increasing the effectiveness of EVD's in removing blood and perhaps controlling ICP. If validated by a clinical trial, our therapy would offer the first-ever clinically directive intervention for this lethal disease. We seek support for a Phase III RCT trial using EVD and rt-PA as IVH treatment. New human safety and dose-finding data demonstrate the concept that rapid removal of IVH clot can be associated with clinically important improvements in morbidity and mortality (>45% mRS 0-3). This is a strong signal that we can translate IVH animal models to human treatment with robust beneficial effects on level of consciousness, ICU treatment intensity, survival, and lowered neurologic morbidity burden as measured by functional performance. The literature, our data, and prior NINDS ICH and NINDS health disparities reviews, support the need for a pivotal Phase III trial, investigating the benefits of removal of IVH clot by comparing use of EVD plus rt-PA vs. EVD alone. We can potentially save lives and improve outcome of brain hemorrhage survivors which now disproportionally burdens minorities, women and the elderly. This trial has robust potential to add an average of 1.7 Qualy's per subject treated making the economic impact substantial. Once we provide critical evidence, generalization to a wide range of hospitals, using SPOTRIAS and newer networks, would be technically straightforward as the interventions and expertise to perform this therapy are already widespread. The planning grant has supported a smooth transition from our completed Phase II trials to the definitive Phase III trial. We are now fully operational and in position to perform without delay in early 2009. PUBLIC HEALTH RELEVANCE: Brain hemorrhage is the most fatal form of stroke with a 50-80% mortality rate in patients with both ICH and IVH hemorrhage extension. This disease disproportionately burdens minorities, women and the elderly. Dose finding and human safety data demonstrate that when a clot is removed rapidly from the ventricle using an EVD and rt-PA administration as treatment, functional and physiologic benefits can be seen (good mRS 0-3 >45%). If the clinical trial we propose validates our theory it would offer the first-ever clinically directive intervention for this lethal disease, potentially saving lives and improving the functional outcomes of brain hemorrhage survivors including their quality of life.